The overall task of the Neuropathology Core is to acquire, characterize and distribute tissues and cells to the Research Projects. Three Specific Aims are proposed. The First Specific Aim deals with the histological examination, including morphometric and immunohistochemical studies, of brains from the tansgenic mouse models of fatal familial insomnia and the familial subtype of Creutzfeldt-Jakob disease with the D178N mutation of the prion protein gene, with or without inoculation of infectious, protease-resistant prion protein. These findings will be compared with those observed in the corresponding human diseases which we have extensively studied. These mouse models will be developed in Research Project 1. In the Second Specific Aim, we will initially characterize the protease-resistant fragments of the prion protein (PrP) that are generated by the protease treatment. This examination will be performed in brain tissue samples that we have recently acquired and that we will acquire in the coming years under Specific Aim 3 (see below). Tissues to be examined include samples from inherited prion diseases such as those linked to the E200K, V2101, P102L point mutations, and the 120 base pairs (bp), 144 and 96 insertional mutations. In addition, 9 ~iatrogenic~ cases and 28 newly acquired sporadic cases of Creutzfeldt-Jakob disease will be examined. The studies of this Specific Aim will serve two purposes: 1) They will provide an initial characterization of the protease-resistant PrP fragments of newly acquired cases for subsequent sequencing and other analyses in Research Project 3; 2) They will help to establish the number of types of protease-resistant PrP, also called prion strains, in the three forms of human prion disease, the inherited and sporadic forms as well as the form acquired by infection. By revealing number and variety of protease-resistant PrP expressed in human prion diseases this study, in turn, will provide insight into the mode of formation of the protease-resistant PrP in sporadic Creutzfeldt-Jakob disease. In the Third Specific Aim, the Core will advertise for, collect, diagnose, PrP genotype and store tissues and cell lines from subjects having or suspected of having a prion disease. These tissues will support research conducted at the three research projects of this program project and at other institutions when requested. During the latest three years, we have been acquiring on average 60 samples per year. The continuous acquisition and characterization of new cases of prion diseases goes beyond the scope of providing necessary tissues and cells to the research projects proposed in this application; it also serves the important purpose of monitoring whether atypical forms of dementia or other atypical neurodegenerative diseases belong to the group of prion disease.